Cutaneous melanoma deriving from the transformation of melanocytes is one of the most lethal cancers among young adults. Its incidence has increased at a dramatic rate during the last decades. Melanoma has a high capability of invasion and rapid metastasis to other organs. The prognosis of metastatic melanoma is extremely pejorative, as the various protocols of chemotherapy or immunotherapy have not shown real survival benefit. Indeed, at the ganglionic metastatic stage, the forecast deteriorates considerably with a survival rate after 5 years of 50%. At the stage of visceral metastases, the forecast is catastrophic with a median of survival of 6 months. Therefore, the melanoma, which represents only 5% of the cutaneous cancers, represents 80% of the deaths associated to this type of cancer. With an incidence, which doubles every ten years (10000 new cases in France in 2007), the melanoma constitutes a real problem of public health. Finally, even if recently encouraging results were obtained with vemurafenib and dabrafenib, two inhibitors of the B-Raf pathway, the responses remain transitory. Indeed, vemurafenib and dabrafenib target only melanomas mutated on B-Raf (approximately 50% of the metastatic melanomas). Unfortunately, after a short period of regression, the melanoma acquires in all cases, a resistance against the drug and the metastases develop again, increasing only about 2 months the life expectancy of the patient. The identification of these mechanisms of resistance is now the subject matter of numerous works but no study managed to clearly identify the mechanisms involved.
Recently, the anti-CTLA4 antibody ipilimumab able to reactivate the immune response of the patient was developed for the treatment of melanoma. However, this approach provides an objective response in only 10 to 15% of the patients.
The identification of new candidate molecules is thus a major aim for the development of specific biotherapies.
The inventors of the instant invention were initially interested in a family of molecules used in the treatment of the type 2 diabetes, the thiazolidinediones (TZD). The effect of PPAR gamma on glucose metabolism is mediated by activation of nuclear receptor, PPAR gamma.
The inventors have previously shown that some TZD led to a massive death of the cells in in vitro as well as in in vivo models of melanoma independently of PPAR gamma activation.
Taken together, the inventors synthesized and identified a family of compounds derived from TZD that led to a loss of viability of the melanoma cells.
The compounds of the inventions thus show a high potency in vitro as well as in vivo models of melanoma. Interestingly, although the compounds of the invention present structure similarities with dabrafenib, their signaling pathways and their mechanisms of action are totally different from those of dabrafenib.
In addition, it appears that the compounds of the invention are also efficient on several other cancers namely prostate, breast and colon indicating that these molecules may be active in all type of cancers.